title: O-GlcNAc transferase inhibits LPS-mediated expression of inducible nitric oxide synthase through an increased interaction with mSin3A in RAW264.7 cells.
abstract: O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT), which catalyzes the addition of a single β-N-GlcNAc unit to target proteins, has been shown to act as a transcriptional regulator. In the current study, we discovered that OGT exerted inhibitory effects on the LPS-driven activation of NF-κB and inducible nitric oxide synthase (iNOS). In response to LPS, OGT exhibited an increased interaction with the transcriptional corepressor mammalian Sin3A (mSin3A). Furthermore, mSin3A, histone deacetylase (HDAC)1, and HDAC2 displayed increased binding to the iNOS promoter in response to LPS. Treatment with GlcN, in contrast, inhibits LPS-induced inflammation and decreased LPS-mediated recruitment of OGT, mSin3A, and HDACs. LPS treatment also resulted in the hypo-O-GlcNAcylation of mSin3A, which was reversed by GlcN. When the effect of the HDAC inhibitor trichostatin A (TSA) on LPS- and/or GlcN-mediated iNOS protein/mRNA induction was investigated, the results revealed that TSA dose dependently enhanced iNOS expression in response to LPS and/or GlcN. In addition, histone acetyltransferases, p300, and cAMP response element-binding protein-binding protein (CBP) enhanced LPS- and/or GlcN-induced iNOS protein expression. These results collectively suggest that OGT inhibits LPS-driven NF-κB activation and subsequent iNOS transcription by modulating histone acetylation either directly or indirectly.
authors.affiliation: Department of Physiology and Biophysics, College of Medicine, Inha University, Incheon, Korea.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Hwang
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Hwang
authors.forename: Song-Yi
authors.initials: SY
authors.lastname: Kim
authors.forename: Inn-Oc
authors.initials: IO
authors.lastname: Han
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D015870:Gene Expression; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D054730:Protein Interaction Domains and Motifs; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D014158:Transcription, Genetic
chemical_list: D006657:Histones; D008070:Lipopolysaccharides; D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D051548:Histone Acetyltransferases; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex
keywords: O-GlcNAc; OGT; c-Rel; mSin3A